The expression of neu oncoprotein was assayed by immunohistochemistry (IHC) on 245 paraffin-embedded, Stage I and II breast cancers from patients treated at the City of Hope between the years 1980 and 1987. Only cases showing membrane staining were scored as positive. Fifty-four (22%) of the tumors stained positively for neu. Probability of disease-free survival (DFS) and overall survival (OS) was compared based on neu positivity and other prognostic factors. Overall, DFS and OS did not differ significantly among neu-positive and neu-negative cases. However, when only cases with favorable (Stages I and II) nuclear grade were analyzed, OS and DFS were significantly lower in neu-positive cases, with a 9-fold increase in risk of death and a 3-fold increase in risk of relapse. Our findings suggest that immunohistologic study of neu oncoprotein may help to define patients at greater risk among low-stage/low-nuclear-grade patients with breast cancer, a group hitherto recognized as having a good prognosis.